TLR4 信号的激活通过诱导线粒体 ROS 产生促进胃癌进展。,Cell Death & Disease

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TLR4 信号的激活通过诱导线粒体 ROS 产生促进胃癌进展。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2013-Sep-12 , DOI: 10.1038/cddis.2013.334
X Yuan ₁ , Y Zhou , W Wang , J Li , G Xie , Y Zhao , D Xu , L Shen

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慢性感染，如幽门螺杆菌感染，与胃癌 (GC) 的发展有关。病原体相关的分子模式可以通过 GC 中的 Toll 样受体 (TLR) 触发炎症反应。在这里，我们发现 Toll 样受体 4 (TLR4) 在 GC 细胞中高度表达，并且与 GC 的侵袭性有关。脂多糖 (LPS) 与 GC 细胞上 TLR4 的结合增强了增殖而不影响细胞凋亡。在 GC 中激活 TLR4 信号后，会诱导更高水平的活性氧 (ROS)。使用氧化酶抑制剂和抗氧化剂，我们发现线粒体 ROS (mROS) 是 TLR4 刺激 ROS 生成的主要来源。这种升高的 mROS 产生可以被二亚苯基碘鎓 (DPI) 抑制，并且阻止 mROS 产生而不是 ROS 中和导致细胞周期停滞和线粒体潜能丧失，这是细胞活力降低的合理原因。此外，由于 TLR4 信号传导增加的 mROS 导致 Akt 磷酸化和 NF-κB p65 核易位的激活。总之，这些结果揭示了一种将先天免疫信号与 GC 细胞增殖联系起来的新途径，暗示 mROS 是细胞存活信号的重要组成部分，并进一步建立线粒体作为 GC 治疗的枢纽。

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Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production.

Chronic infection, such as Helicobacter pylori infection, has been associated with the development of gastric cancer (GC). Pathogen-associated molecular patterns can trigger inflammatory responses via Toll-like receptors (TLRs) in GC. Here we showed that Toll-like receptor 4 (TLR4) was highly expressed in GC cells and was associated with the aggressiveness of GC. The binding of lipopolysaccharide (LPS) to TLR4 on GC cells enhanced proliferation without affecting apoptosis. Higher level of reactive oxygen species (ROS) was induced after activation of TLR4 signaling in GC. Using oxidase inhibitors and antioxidants, we found that mitochondrial ROS (mROS) was major source of TLR4-stimulated ROS generation. This elevated mROS production can be inhibited by diphenylene iodonium (DPI), and the blocking of the mROS production rather than ROS neutralization resulted in cell cycle arrest and the loss of mitochondrial potential, which were plausible reason for decreased cell viability. Furthermore, the increased mROS owing to TLR4 signaling resulted in the activation of Akt phosphorylation and NF-κB p65 nuclear translocation. Altogether, these results reveal a novel pathway linking innate immune signaling to GC cell proliferation, implicate mROS as an important component of cell survival signals and further establish mitochondria as hubs for GC therapies.

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